Hypoxic regions occur widely in human tumours, and the cells in these regions are relatively resistant to ionising radiation. This leads to frequent recurrence of tumours after radiotherapy, due to the survival of these radioresistant cells. The use of oxygen-mimetic radiosensitizers has also been widely explored, but with mixed success. The existence of such hypoxic regions, restricted essentially to tumour tissue, has resulted in the development of bioreductive prodrugs (hypoxia-activated prodrugs; HAP) capable of being activated by enzymatic reduction only in these hypoxic regions. The majority of these prodrugs are activated to a transient one-electron intermediate in all cells, but this intermediate is re-oxidised by molecular oxygen in normal tissue, allowing activation to a toxic species to occur only in fully hypoxic cells.
The improved targeting ability of modem radiotherapy to deliver ionizing radiation only to the tumour field has suggested the possibility of using the reducing equivalents from this radiation, rather than cellular enzymes, to activate prodrugs (radiation-activated prodrugs; RAP). The activation of these prodrugs would thus be confined to hypoxic regions within the radiation field, providing a double level of selectivity. Such a mechanism of activation has other theoretical advantages over HAP [Wilson et al., Anticancer Drug Design, 13: 663–685, 1998]. These include:                Lack of collateral activation in partially hypoxic normal tissues (outside the radiation field).        Use of the whole of the hypoxic tumour volume (including necrotic regions with no active reductases or reducing cofactors) to activate the prodrug.        Avoidance of dependence on possibly varying enzyme levels, and degree of effectiveness as enzyme substrates.        
While there have been many reports on HAP [for example reviews by Denny, Lancet Oncol. 2000, 1, 25–29; Stratford and Workman, Anti-Cancer Drug Design 1998, 13, 519–528; Denny et al., Brit. J. Cancer, 1996, Suppl. 27, 32–38], there has been relatively few reports on RAP. An approach to using therapeutic ionizing radiation to activate a prodrug was reported [Nishimoto et al., J. Med. Chem. 1992, 35, 2711; Mori et al; J. Org. Chem., 2000, 65, 4641–4647; Shibamoto et al., Jpn. J. Cancer Res., 2000, 91, 433–438; Shibamoto et al., Int. J. Rad. Oncol. Biol. Phys., 2001, 49, 407–413], employing radiolytic activation of a 5-fluorouracil (5-FU)-based compounds, such as compound A.

However, doses of radiation used during radiotherapy (typically 2 Gy/day) provide a total primary radical yield of only approximately 1.2 μmol/kg. Only about half of this radical yield comprises reducing species capable of activating prodrugs by reduction. Thus the released effector 5-FU; illustrated as compound B above, is not sufficiently potent to ensure clinically effective concentrations following therapeutic levels of radiation.
The use of metal complexes of bidentate mustards, such as compound C illustrated below, as RAP has also been reported [Denny et al., PCT NZ96/00085, 19 Aug. 1996]. However, the released mustards, such as compound D illustrated below, are also unlikely to be sufficiently potent (IC50−s around 1 μM to ensure clinically effective concentrations following therapeutic levels of irradiation.

It is therefore an object of the invention to provide heterocycles and their metal complexes either as prodrugs that are activated under hypoxic conditions by enzymes or other endogenous reducing agents or by therapeutic radiation, or at least to provide the public with a useful choice.